Rhoifolin Alleviates Ulcerative Colitis by Targeting NMNAT1 and Activating SIRT1-FOXO1 Signaling to Enhance ILC3s...

Area of Science:

• Immunology
• Gastroenterology
• Pharmacology

Background:

• Ulcerative colitis (UC) presents limited treatment options, especially for reinforcing intestinal barrier integrity while maintaining immune balance.
• There is a need for novel therapeutic strategies that selectively target immune responses in the gut.

Purpose of the Study:

• To investigate the therapeutic potential of Rhoifolin in a mouse model of ulcerative colitis.
• To elucidate the underlying molecular mechanisms by which Rhoifolin exerts its protective effects on the intestinal barrier.

Main Methods:

• Administration of Rhoifolin to mice with DSS and TNBS-induced colitis.
• Analysis of ILC3s function, cytokine production (IL-22), and epithelial barrier integrity.
• Integrated transcriptomics and metabolomics to identify molecular targets and pathways.
• Molecular docking, dynamic simulations, and biochemical assays to validate target interactions (NMNAT1, SIRT1, FOXO1).

Main Results:

• Rhoifolin dose-dependently alleviated colitis symptoms in mice.
• Rhoifolin selectively enhanced ILC3s effector function and IL-22 production without altering ILC3s populations.
• The compound targets NMNAT1, activating the NMNAT1-NAD+-SIRT1-FOXO1 axis, which promotes IL-22 transcription and reinforces the epithelial barrier.
• Rhoifolin treatment led to increased NAD+ levels, SIRT1 activity, and FOXO1 nuclear translocation, enhancing IL-22 expression.

Conclusions:

• Rhoifolin demonstrates significant therapeutic efficacy in preclinical models of ulcerative colitis.
• The study uncovers a novel immunometabolic and epigenetic regulatory axis (NMNAT1-NAD+-SIRT1-FOXO1) crucial for intestinal barrier protection.
• Empowering ILC3s through Rhoifolin represents a promising therapeutic strategy for ulcerative colitis.